title: The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice.
abstract: Catalytic oligonucleotides, known as DNAzymes, are a new class of nucleic acid-based gene therapy that have recently been used in preclinical animal studies to treat various cancers. In this study the systemic distribution, pharmacokinetics, and safety of intravenously administered anti-MMP (matrix metalloproteinase)-9 DNAzyme (AM9D) were determined in healthy FVB and in MMTV-polyoma virus middle T (PyMT) transgenic mice bearing mammary tumors. MMP-9 is known to be involved in tumor cell development, angiogenesis, invasion, and metastasis. Sulfur-35 ((35)S) labeled ([(35)S]-AM9D) administered intravenously, without the use of carrier molecules, to healthy and mammary tumor bearing MMTV-PyMT transgenic mice distributed to all major organs. The order of percentages of [(35)S]-AM9D accumulation in different organs of healthy and MMTV-PyMT mice were blood>liver>kidney>lung>spleen>heart and mammary tumor>blood≈liver>kidney>spleen>lung>heart, respectively. The amount of AM9D accumulated in mammary tumors 2 hours post injection was 0.6% and 0.2% higher than in either blood or liver, respectively, and its rate of initial clearance from mammary tissue was at least 50% slower than the other organs. Approximately 43% of the delivered dosage of [(35)S]-AM9D was cleared from the system via feces and urine over a period of 72 hours. No evidence of acute or chronic cytotoxicity, local or widespread, associated with AM9D treatment (up to 75 mg AM9D /kg of body weight) was observed in the organs examined. These data suggest that DNAzyme in general and AM9D in particular can be used systemically as a therapeutic agent to treat patients with breast cancer or other metastatic and surgically inaccessible tumors.
authors.affiliation: 1 Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center , Memphis Tennessee.
authors.forename: Miranda A
authors.initials: MA
authors.lastname: Hallett
authors.forename: Pooja
authors.initials: P
authors.lastname: Dalal
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Sweatman
authors.forename: Tayebeh
authors.initials: T
authors.lastname: Pourmotabbed
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D021881:DNA, Catalytic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011120:Polyomavirus; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D021881:DNA, Catalytic; C000590215:anti-MMP-9 DNAzyme; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse